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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:551.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Physical Training Improves Flow-Mediated Dilation in Patients With the Polymetabolic Syndrome

Alea Lavreni; Barbara Gui Salobir; Irena Keber

From the University Medical Centre, Department of Angiology, Ljubljana, Slovenia.

Correspondence to Alea Lavreni, Lek d.d., Research and Development, Celovka 135, 1526 Ljubljana, Slovenia. E-mail: alesa.lavrencic{at}lek.si

	Abstract

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Abstract—Endothelial dysfunction that can be detected as impaired flow-mediated dilation by ultrasonography is an early event in atherogenesis and has been demonstrated in healthy subjects with risk factors for atherosclerosis many years before the appearance of atheromatous plaques. We examined the influence of physical training on flow-mediated dilation in patients with the polymetabolic syndrome. Twenty-nine asymptomatic men aged 40 to 60 years with the polymetabolic syndrome were randomly divided between the control group and the training group, which trained 3 times a week for 12 weeks. On high-resolution ultrasound images, the diameter of the brachial artery was measured at rest, after reactive hyperemia (causing flow-mediated, endothelium-dependent dilation), and after sublingual glyceryltrinitrate (causing endothelium-independent vasodilation) in all subjects before and after the training period. The training program induced an increase of 18% in physical fitness. Flow-mediated dilation increased from 5.3±2.8% to 7.3±2.7% (P<0.05). There was no change in body mass index, blood pressure, insulin resistance, lipids, and big endothelin-1 in either group. Flow-mediated dilation measured before training was negatively correlated with resting heart rate, waist-to-hip ratio, and insulin resistance. Resting heart rate emerged as the only independent determinant, which explained 22% of the variation in flow-mediated dilation. In conclusion, our findings suggest that a 3-month physical training program, which improved maximal exercise capacity, enhances flow-mediated dilation in patients with the polymetabolic syndrome.

Key Words: physical training • flow-mediated dilation • polymetabolic syndrome • ultrasonography • conduit arteries

	Introduction

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Exercise has well-known benefits regarding the reduction in cardiovascular morbidity and mortality.^{1 2 3} The results of many studies have shown beneficial effects of physical training on several risk factors for atherosclerosis.^{4 5 6 7} However, there also seems to be a direct effect of training on the vascular endothelium. Endothelial cells play an important role in the modulation of vascular tone by releasing an endothelium-derived relaxing factor, identified as nitric oxide (NO).⁸ The endothelial dysfunction, which is marked by an impaired ability of the artery to dilate in response to increased shear stress and several pharmacological stimuli, has been found in asymptomatic subjects with risk factors for atherosclerosis.^{9 10 11}

There is considerable evidence that increased shear stress via increased blood viscosity,¹² heart rate and pulse pressure,¹³ and blood flow,¹⁴ which can all be a result of exercise, increases the production of NO from the arterial endothelium. Recent evidence suggests that these factors may contribute to persistent NO production in the period between exercise bouts. Experiments in animal models have demonstrated that chronic exercise caused an increase in NO synthase gene expression and endothelial release of NO, which was associated with improved endothelium-dependent dilation.^{15 16} In humans, there have been few studies investigating the effects of aerobic exercise training on endothelium-dependent dilation. These studies were performed in healthy subjects¹⁷ or patients with chronic heart failure,^{18 19 20} and they showed promising results.

The aim of our study was to discover whether physical training improves flow-mediated dilation in asymptomatic patients with the polymetabolic syndrome, which includes a cluster of cardiovascular risk factors: insulin resistance, hypertriglyceridemia, reduced HDL cholesterol, arterial hypertension, and increased thrombogenic potential.^{21 22 23}

	Methods

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Subjects
Thirty asymptomatic men aged 40 to 60 years with the polymetabolic syndrome were selected from the outpatients regularly attending a lipid clinic, a diabetic clinic, or a hypertension clinic. Polymetabolic syndrome was diagnosed on the basis of fulfillment of at least 2 of the following criteria²¹ : impaired glucose tolerance (determined by the oral glucose tolerance test), dyslipoproteinemia (serum triglycerides >2.3 mmol/L and HDL cholesterol <0.9 mmol/L), and high blood pressure (>140/90 mm Hg). All subjects were nonsmokers. Before the study they did not perform exercise more than once a week. They had no symptoms of coronary heart disease, peripheral arterial occlusive disease, or other conditions that might represent a contraindication for physical training. With laboratory testing we excluded anemia. Written, informed consent was obtained from all subjects. The study was approved by the State Ethics Committee.

Clinical Examination
Before and after the intervention period, blood pressure, heart rate, and anthropometric parameters were determined. All parameters were determined by a single observer. Systolic and diastolic blood pressures were measured with a mercury sphygmomanometer after a minimum of 10 minutes of rest in a sitting position. Heart rate at rest was taken from an ECG recording. The body mass index was calculated as weight in kilograms divided by the square of the height in meters. Waist circumference was measured midway between the lower rib margin and the iliac crest, at the end of a normal expiration. Hip circumference was evaluated as the largest measurement in a horizontal plane around the buttocks. The waist to hip ratio was then calculated.

Maximal Exercise Testing
Maximal exercise testing on a bicycle ergometer was performed before and after the intervention period. A constant number of pedal revolutions (60 to 80 per minute) was maintained while increasing the resistance. The initial workload was 25 W, with 25-W increments every 3 minutes. Heart rate was monitored continuously, and blood pressure was measured at the start of the test and at the end of each power increment. The indications for terminating exercise testing were the appearance of symptoms (exhaustion, shortness of breath, chest pain, or pain in the legs), physical signs (an elevation of blood pressure >250/120 mm Hg, a decrease of systolic blood pressure by >10 mm Hg, an attainment of maximal heart rate, or a decrease of heart rate), or ECG changes (ST-segment depression by >3 mm, ST-segment elevation by >1 mm, or arrhythmia).²⁴ Patients in whom exercise testing suggested coronary heart disease were excluded from the study, as were the patients in whom any kind of pain, which could represent an obstacle to physical training, appeared during the exercise testing.

Physical Training
The subjects were randomly divided between the training and the control group. The training group was scheduled for aerobic exercise 3 times weekly for 12 weeks, supervised by a physiotherapist. Each session consisted of a 20-minute warm-up period and 30 minutes of intense exercise on a bicycle ergometer at 80% of the previously determined maximum heart rate. This intensity of training was attained gradually in a period of 2 weeks, and, as the aerobic capacity of the subjects improved, the workload was increased to keep the pulse rate at a desired level. The heart rate was determined by palpation of the carotid pulse by the subjects themselves.

Subjects in the control group were asked to maintain their habitual activities. In the training group, 14 subjects completed the study; their attendance at training sessions was 86%. One subject stopped with the training program earlier, mainly due to lack of motivation. In the control group, all 15 subjects completed the study.

Blood Sampling
Blood for analysis was sampled before the intervention period and 3 to 7 days after the last training session. Blood was collected in the morning after a 12-hour overnight fast. Blood samples were drawn from the antecubital vein. Blood for the analysis of glucose, insulin, lipids, apolipoproteins A-I and B, and lipoprotein(a) [Lp(a)] was collected without additives. For the analysis of big endothelin-1, the blood was collected in citrated tubes. The blood was centrifuged, and samples of serum and plasma were transferred to small plastic vials and stored at -70°C until analyzed.

Laboratory Methods
The concentrations of serum glucose, total and HDL cholesterol, and triglycerides were determined by standard colorimetric assays (Ektachem 250 Analyzer, Eastman Kodak Co). LDL cholesterol was calculated from the Friedewald formula.²⁵ Apolipoproteins A-I and B were determined by immunonephelometric assays²⁶ (Behring). Lp(a) was measured by an ELISA method²⁷ using commercial kits (TintElize Lp(a), Biopool). Insulin was determined by an immunoradiometric assay²⁸ using commercial kits (INSI-CTK irma, Sorin Diagnostics). Insulin resistance was estimated by homeostasis model assessment.²⁹ Big endothelin-1 was measured by an enzyme immunoassay³⁰ using commercial kits (Biomedica).

Ultrasound Measurements
Before and after the intervention period, each subject underwent noninvasive study of a brachial artery to assess endothelial and smooth muscle responses. The high-resolution B-mode Diasonics VST ultrasound system with a 10-MHz linear-array transducer was used to measure changes in arterial diameter in response to reactive hyperemia (with increased flow producing an endothelium-dependent stimulus to vasodilation) and to glyceryltrinitrate ([nitroglycerin], GTN, an endothelium-independent vasodilator). Each subject rested in the supine position for 10 minutes before the first scan and remained supine throughout the study. The right brachial artery was scanned in longitudinal section above the elbow to find the clearest images of the anterior and posterior wall layers. All measurements were performed with the same position of the transducer and the arm. The diameter was always measured at end-diastole, which was determined with simultaneous monitoring of the ECG (concurrent with onset of the QRS complex). Blood flow velocity was measured using a pulsed Doppler signal at a 68° angle to the vessel. Arterial blood flow was calculated from blood flow velocity and arterial diameter. After a baseline brachial artery diameter and blood flow velocity had been measured, a pneumatic tourniquet was placed around the forearm and inflated to a pressure of 300 mm Hg for 4 minutes, followed by release. Blood flow velocity was measured again 15 seconds after cuff deflation, and arterial diameter was measured 45 to 60 seconds after cuff deflation. Ten minutes later, baseline measurements were repeated. The last measurements were taken 3 to 4 minutes after administration of 0.5 mg of sublingual GTN.

All measurements were carried out by the same investigator, who was blinded to the subjects’ characteristics. For assessment of the reproducibility of measurements, 10 subjects were selected randomly for repeated measurements of endothelium-dependent dilation. The correlation coefficient between the absolute differences and mean values of paired measurements was 0.86 (P<0.05).

The flow-mediated dilation was expressed as a percentage change of diameter after reactive hyperemia relative to the baseline scan. Likewise, the GTN-mediated dilation was expressed as a percentage change of diameter after GTN administration relative to the baseline scan.

Statistical Analysis
Variables showing a normal distribution, which was tested by the Kolmogorov-Smirnov test, were expressed as means and SDs. Asymmetrically distributed variables were described by median and range. Baseline characteristics of the subjects in both groups were compared by the unpaired Student’s t test for normally distributed variables, by the Mann-Whitney U test for asymmetrically distributed variables, and by the Fisher exact test for attributive variables. The variables measured before and after the intervention period were compared by the paired Student’s t test. For correlation analysis, Pearson’s correlation coefficient was calculated for normally distributed variables and Spearman’s rank-correlation coefficient for other variables. Multiple regression analysis was carried out to find independent determinants for the variations in flow-mediated dilation. The criterion for statistical significance was a P value <0.05. All calculations were performed by the Statistica computer program (StatSoft Inc, 1995).

	Results

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Clinical and Biochemical Parameters
The average age of subjects was 53±5 years in the training group and 51±7 years in the control group (nonsignificant difference). There were also no significant differences in medication between the training group (3 subjects were receiving angiotensin-converting enzyme inhibitors; 5, calcium antagonists; 2, ß-blockers; 1, an -blocker; and 4, statins) and the control group (3 subjects were receiving angiotensin-converting enzyme inhibitors; 4, calcium antagonists; 1, a ß-blocker; 1, an -blocker; 3, statins; and 4, fibrates). The medication had not been changed during the last 6 months before the study and remained the same during the study. Table 1 shows the clinical and biochemical parameters before and after the training period in the training and control groups. At the beginning of the study, there was no difference between the groups in the observed parameters. After the training period, the maximal exercise capacity improved only in the training group by 18%.

View this table: [in this window] [in a new window]   Table 1. Clinical and Biochemical Parameters in Patients With Polymetabolic Syndrome Before and After the Training Period

Vascular Studies
There was an improvement of 2% in flow-mediated dilation in the training group after the training period (Table 2). There was no significant change in the GTN-mediated dilation or other hemodynamic parameters.

View this table: [in this window] [in a new window]   Table 2. Hemodynamic Parameters of the Brachial Artery at Rest, After Reactive Hyperemia, and After Sublingual Nitroglycerin (GTN) Before and After Physical Training

Correlations
The baseline flow-mediated dilation was negatively correlated with the resting heart rate (r=-0.49, P<0.01) and waist-to-hip ratio (r=-0.40, P=0.03). The negative correlation with insulin resistance almost reached statistical significance (r=-0.34, P=0.07).

In the multiple regression model, which included the resting heart rate, waist-to-hip ratio, and insulin resistance, the baseline flow-mediated dilation turned out to be independently related only to resting heart rate (partial r=-0.49, P<0.01; R²=0.22, P<0.01).

	Discussion

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This is the first study to provide evidence of improved flow-mediated dilation in conduit vessels after aerobic training performed in asymptomatic subjects with risk factors for atherosclerosis. The baseline flow-mediated dilation was negatively correlated with the resting heart rate, waist-to-hip ratio, and insulin resistance, of which only resting heart rate emerged as an independent determinant of flow-mediated dilation. Although many of our subjects were on medications that alter the resting heart rate, this correlation could speak in favor of the view expressed by others³¹ that a chronically elevated heart rate may be directly associated with injury to the endothelium due to the intensified pulsatile nature of arterial blood flow.

In our study, there was no change in insulin resistance, plasma lipids, or arterial blood pressure after training, which means that the improved endothelium-dependent dilation could not be explained by alterations in any of the known risk factors for atherosclerosis, which have been shown to be connected with impaired endothelium-dependent dilation.^{9 10 11} There was also no change in the plasma concentration of big endothelin-1, which is a precursor of a potent vasoconstrictor, endothelin-1.

Recent experimental data demonstrate that NO synthase gene expression in endothelial cell cultures is increased after exposure to increased shear stress³² and that chronically increased blood flow causes an increased endothelial release of NO.¹⁴ Moreover, a 10-day training program increased the vascular NO production and NO synthase gene expression in a dog model¹⁶ and was associated with increased endothelium-dependent dilation of coronary arteries.¹⁵ These experimental observations would support the notion that repetitive increases in vascular shear stress caused by physical training exert an upregulation of the NO synthase gene, which in turn provides enhanced synthesis and release of NO, resulting in an improvement of endothelial function. In our study, the patients performed leg training, whereas the improved flow-mediated dilation was measured on the brachial artery. This observation could be explained by the increased shear stress, which also occurs in the forearm vascular bed during leg exercise. This is supported by the findings of Kingwell et al,¹⁷ who showed that such training increased forearm blood flow and blood viscosity in the immediate postexercise period. Increased heart rate and pulse pressure, which are also induced by exercise, could contribute to increased shear stress as well.³³

Only a few studies investigating the influence of physical training on endothelium-dependent dilation have been performed in humans, and most of them showed positive results. Kingwell et al¹⁷ showed that 4 weeks of moderate cycle training performed for 30 minutes 3 times a week in healthy subjects without cardiovascular risk factors significantly increased the basal release of NO in the forearm vascular bed, but no change in forearm blood flow in response to acetylcholine (an endothelium-dependent dilator) was observed, which could be due to the shorter duration of training compared with the one in our study. In 2 other studies,^{18 19} the influence of daily handgrip exercise on the endothelium-dependent dilation of arteries of the same arm was studied in patients with chronic heart failure, and after 4 weeks of training, an improvement in this parameter was found. Hambrecht et al²⁰ showed that 6 months of cycle training improved both basal endothelial NO formation and acetylcholine-mediated endothelium-dependent dilation of the skeletal muscle vasculature in patients with chronic heart failure. In most of the previous studies,^{17 19} plethysmography was used to measure blood flow in conduit arteries, which reflects changes in the resistance arteries. In contrast, we determined endothelial function by measurement of the change in diameter of the conduit artery.

Until now there has been no prospective study to answer the question whether the improved endothelium-dependent dilation reduces cardiovascular morbidity and mortality. However, based on known data, it could be assumed that improved endothelium-dependent dilation is connected with a deceleration of the progression of atherosclerosis and its complications. A reduced release of NO from endothelial cells appears not only to be an indicator of atherosclerosis but also to contribute to its initiation and progression. An impaired production of NO leads to vasoconstriction, which results in turbulent flow and damage to the endothelium.³⁴ NO also inhibits platelet adherence and aggregation, smooth muscle proliferation, and endothelial cell–leukocyte interactions.^{35 36} All of these factors are known to contribute to the progression of atherogenesis.

In conclusion, our study showed the beneficial effects of physical training on early functional atherosclerotic changes of the arterial endothelium in patients with the polymetabolic syndrome, who are at great risk of cardiovascular diseases. This could be another indirect argument in favor of encouraging physical exercise as a therapeutic measure in patients with cardiovascular risk factors.

Received March 23, 1999; accepted July 21, 1999.

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